FOXC1 expression in meningiomas.
Authors: Michelle Wedemeyer, Joanne Xiu, Phillip Walker, Jasmeet Kaur, Christian Davidson, Manmeet Singh Ahluwalia, Ashley Love Sumrall, Gabriel Zada
Journal: Journal of Clinical Oncology (2023)

2074 Background: Meningiomas account for nearly 1/3 of brain tumors and are characterized by a low mutational burden and dysregulation of DNA methylation. The promoter of FOXC1 is hypomethylated relative to dura in meningiomas of all grades and knockdown of FOXC1 in murine models causes craniofacial hypoplasia and absent frontal dura, suggesting a role as a meningeal identity gene. Here we perform a multi-omic analysis of FOXC1 expression in a large cohort of meningiomas. Methods: A total of 555 meningiomas (148 grade I, 255 grade II and 87 grade III) were analyzed with next-generation DNA sequencing (592 gene NextSeq panel; n=150 or Agilent WES whole exome sequencing, n=405) and whole mRNA (WTS, NovaSeq, 555) at Caris Life Sciences (Phoenix, AZ). Top quartile transcripts per million (TPM) for FOXC1 expression were considered high (FOXC1-H) and bottom quartile low (FOXC1-L). Immune cell infiltration was estimated using RNA deconvolution by QuantiSeq to calculate median cell fractions (MCF) or positive percentages (PP). Data were analyzed using X2/Fisher’s-exact/Mann-Whitney U tests. A p-value&lt;0.05 after BH correction was considered significant. Results: Median FOXC1 expression was 33 TPM. Expression of FOXC1 transcript was higher in lower grade tumors (I: 34, II: 29, III: 27, q&lt;0.05). NF2 mutations were significantly more common in FOXC1-L than FOXC1-H tumors (45% vs. 68%, q&lt;0.05). Although a higher percentage of FOXC1-H meningiomas harbored TERT promoter mutations (2% vs. 9%, p&lt;0.05) and a higher percentage of FOXC1-L meningiomas harbored a TRAF7 mutation (19%. Vs. 5.5%, p&lt;0.05), these differences were not significant after correction for multiple comparisons. Programmed cell death ligand1 (PD-L1/CD274, 2.27 vs. 492) and MHC-I (HLA-A: 58 vs. 109, HLA-B: 59 vs. 74, and HLA-C: 61 vs. 101) transcripts were more highly expressed in FOXC1-H than FOXC1-L tumors. FOXC1-L tumors exhibited significantly more B cells (MCF: 5% vs. 4%), M1 Macrophages (MCF: 2% vs. 1%), CD8+ T cells (PP: 27% vs. 7%), and a higher interferon gamma transcript signature than FOXC1-H. Infiltrates of NK cells (MCF: 3.5% vs. 4.3%) and dendritic cells (MCF: 6% vs. 8%) were higher in FOXC1-H (all q&lt;0.05). Conclusions: The craniofacial patterning transcription factor FOXC1 was found to be widely expressed in a large cohort of meningiomas and its expression is inversely correlated with WHO tumor grade. Multi-omic analysis reveals a significant relationship between FOXC1 transcript levels and key markers of the immune environment including PD-L1 transcript expression. These data suggest that FOXC1 is a marker of meningiomas in addition to its role as a meningeal identity marker during development. Functional studies are warranted to determine whether FOXC1 is necessary for meningioma growth, whether FOXC1 plays a direct immunomodulatory role in meningiomas, and whether the lower FOXC1 expression levels in high grade tumors represent a more embryonic phenotype.